Determination of malignant spread is the key prognostic factor for oral-cavity cancer and is critical for the development of an adequate treatment plan. Metastases are the primary driver behind over 6,400 annual deaths and a five-year survival rate of only 66% for oral-cavity cancer in America. Thus, accurate and timely assessment of the presence of micrometastases (mMets) is critical for accurate staging and therapy planning. Despite its significant potential morbidity, elective neck dissection (END) is the gold standard for assessing the presence or absence of disease in sentinel lymph nodes (SLNs), the most common location for oral-cavity cancer mMets. Unfortunately, there is currently no effective preoperative or intraoperative method to detect such mMets, and thus there is an urgent clinical need for a point-of-care imaging technology that can be safely and noninvasively implemented to reliably visualize mMets in real-time. The goal of our research is to develop a targeted contrast agent and a noninvasive imaging technique to accurately identify mMets in SLNs with high resolution, a method we refer to as targeted activatable nanodroplet (TAN) molecular ultrasound lymphatic (MUSL) imaging. Our imaging approach promises to deliver a uniquely versatile contrast agent that has a size profile that can be remotely adjusted to allow for both molecularly targeted delivery, requiring a nano-scale agent, and high-contrast, high-resolution imaging at depth with conventional ultrasound, which requires a micron-scale agent. A highly appealing feature of our technology is its use of widely available conventional US imaging with a single injection of an inert and highly biocompatible contrast agent, attributes that support widespread clinical implementation. Our hypothesis is that TANs can be imaged in real-time and with high contrast and resolution using conventional US imaging, yielding immediate diagnostic information for patient staging that will facilitate timely and less- invasive treatment (e.g., eliminate ENDs) and/or to intraoperatively guide surgical/biopsy interventions. Our compelling preliminary data demonstrate synthesis feasibility of stable, nano-sized, molecularly specific TANs that can undergo an ultrasound (US) activatable phase-change transformation to their microbubble (MB) form (~1 ?m), which can be visualized using conventional US imaging. To develop this technology toward detection of SLN mMets from head and neck cancers, we will pursue the following aims: (SA1) develop clinically translatable TANs with optimum acoustic-activation thresholds and with demonstrated molecular specificity to head and neck cancer cells; (SA2) optimize MUSL imaging for high-resolution, quantitative assessment of targeted TANs in cell phantoms; (SA3) validate TAN-MUSL imaging?s ability to detect SLN mMets in an orthotopic murine model of metastatic cancer. This platform has potential to address all disadvantages of the current standard of care by providing a cancer-specific, non-radioactive contrast agent that can be noninvasively and clearly visualized using standard clinical US prior to and during surgery. Such technological advancements promise to make ?leap? improvements in the staging and the treatment of oral-cavity cancers.